The term "electrotransport" as used herein refers generally to the delivery of an agent (eg, a drug) through a membrane, such as skin, mucous membrane, or nails, which delivery is induced by application of an electrical potential. For example, a beneficial therapeutic agent may be introduced into the systemic circulation of a human body by electrotransport delivery through the skin. A widely used electrotransport process, iontophoresis, involves the electrically induced transport of charged ions. Another type of electrotransport, electroosmosis, involves the flow of a liquid, which liquid contains the agent to be delivered, under the influence of an electric field. Still another type of electrotransport process, electroporation, involves the formation of transiently-existing pores in a biological membrane by the application of an electric field, through which pores an agent can be delivered either passively (ie, without electrical assistance) or actively (ie, under the influence of an electric potential). However, in any given electrotransport process, more than one of these processes may be occurring simultaneously to a certain extent.
Accordingly, "electrotransport", as used herein, should be given its broadest possible interpretation so that it includes the electrically induced or enhanced transport of at least one agent, which may be charged, uncharged, or a mixture thereof, regardless of the specific mechanism or mechanisms by which the agent actually is transported.
Electrotransport devices generally use at least two electrodes which are in electrical contact with some portion of the skin, nails, mucous membrane, or other surface of the body. One electrode, commonly referred to as the "donor" or "active" electrode, is the electrode from which the agent is delivered into the body. The other electrode, typically termed the "counter" or "return" electrode, serves to close the electrical circuit through the body. For example, if the agent to be delivered is positively charged, ie a cation, then the anode will be the active or donor electrode, while the cathode serves to complete the circuit. Alternatively, if an agent is negatively charged, ie an anion, the cathode will be the donor electrode. Additionally, both the anode and cathode may be considered donor electrodes if both anionic and cationic agent ions are to be delivered.
Furthermore, electrotransport delivery systems generally require at least one reservoir or source of the agent to be delivered to the body. Examples of such donor reservoirs include a pouch or cavity, a porous sponge or pad, and a hydrophilic polymer or a gel matrix. Such donor reservoirs are electrically connected to, and positioned between, the anode or cathode and the body surface, to provide a fixed or renewable source of one or more agents or drugs. Electrotransport devices also have an electrical power source such as one or more batteries. Typically, one pole of the power source is connected to the donor electrode, while the opposite pole is connected to the counter electrode. In addition, some electrotransport devices have an electrical controller which controls the current applied through the electrodes, thereby regulating the rate of agent delivery. Furthermore, passive flux control membranes, adhesives for maintaining device contact with a body surface, insulating members, and impermeable backing members are some other potential components of electrotransport devices.
Although the advantages of electrotransport delivery are numerous (eg, enhanced transmembrane flux of beneficial agents compared to passive, ie, non-electrically assisted flux; precise control of agent delivery, including patterned delivery, etc.), there are disadvantages under certain application conditions. One potential problem with electrotransport transdermal delivery is skin irritation. For instance, applying electric current through skin under certain conditions has been known to cause skin irritation. See for example, "Skin Biological Issues in Electrically Enhanced Transdermal Delivery", P. Ledger, Advanced Drug Delivery Reviews, Vol. 9 (1992), pp 289-307.
In addition to the level of applied electric current, other factors can cause, or at least contribute to, skin irritation during transdermal electrotransport agent delivery. For example, most electrotransport drug delivery devices use an aqueous solution or suspension of the agent to be delivered, since water is a biocompatible solvent and since many drug salts are water soluble. Under certain conditions, especially in electrotransport devices having electrodes formed of an electrochemically inert (ie, catalytic) material, such as platinum or stainless steel, water hydrolysis tends to occur at the interface between the electrode and the drug solution (donor reservoir) or electrolyte salt solution (counter reservoir). The products of water hydrolysis (ie, hydronium ions are produced by water hydrolysis at the anode and hydroxyl ions are produced by water hydrolysis at the cathode) compete with the drug ions of like charge for delivery into the skin, thereby altering skin pH. Since (i) highly basic or acidic solutions in contact with the skin surface and (ii) highly basic or acidic conditions within the skin itself are known to damage tissue, the pH-altering effects of electrotransport devices, independent of current density effects, can also cause skin irritation.
In order to prevent water hydrolysis, prior art devices used electrodes composed of electrochemically reactive materials (eg, silver anodes and silver chloride cathodes) which materials were oxidized or reduced in lieu of water hydrolysis. See for example Phipps et al U.S. Pat. Nos. 4,744,787 and 4,747,819; Petelenz et al U.S. Pat. No. 4,752,285 and Untereker et al U.S. Pat. No. 5,135,477.
In addition to electrochemically reactive electrode materials, the prior art has also utilized conventional buffering agents to control the pH of the donor and counter reservoirs. See as for example Jacobsen et al U.S. Pat. No. 4,416,274 (sodium phosphate buffers) and Hillman et al U.S. Pat. No. 5,088,978 (citric acid/citrate salt buffers). Although conventional buffers are effective to maintain donor reservoir pH, they introduce undesirable extraneous ions which tend to compete with the drug ions for delivery. For example, when an anodic donor reservoir for delivering a cationic drug D.sup.+ is buffered with a citrate salt (eg, sodium citrate), the citrate buffer absorbs hydronium ions produced by water hydrolysis at the anode but leaves extraneous sodium ions which compete with the drug ions, D.sup.+, for delivery. Whenever a significant amount of competing ions are present, the rate of drug delivery cannot be accurately predicted simply by measuring or controlling the amount of electric current applied by the device.
In response to these problems, the prior art used buffering agents which were substantially immobile. See Sanderson et al, U.S. Pat. No. 4,722,726 and Johnson et al, U.S. Pat. No. 4,973,303.
Most prior art devices used buffering agents to maintain the donor (drug) and counter (electrolyte) reservoirs at pH levels at or near skin pH. For instance, Hillman et al, U.S. Pat. No. 5,088,978, discloses an anodic electrode buffered at pH 4-5 to resist pH changes associated with proton generation from water hydrolysis. This patent further discloses buffering an "indifferent", cathodic electrode at pH 4-7.
The effects of anodic and cathodic pH on selected buffers in iontophoresis are discussed in "Some Hazards of the Sweat Test" by Schwarz, V. et al, Arch. Dis. Childh. (1968) 43,695-701. Carbon and copper electrodes were used in the reported experimentation. This reference indicates that blistering of the skin in contact with either the cathode or anode is dependent upon both the pH and the buffer composition of the anodic and cathodic reservoirs.
However, according to "Structure-Transport Relationships in Transdermal Iontophoresis" by Yoshida et al, Ad. Drug Del. Rev. (1992), 9, 239-264, the preferred pH range for avoiding skin irritation for the donor reservoir, independent of the buffer used, is 3 to 8. Outside this pH range, according to this reference, irritation and/or damage of the stratum corneum can occur.
Thus, literature and patent references have presented overlapping pH ranges for minimizing skin irritation. Certain references have focussed primarily on providing neutral solutions or solutions having pH near that of human skin at both the anodic and cathodic reservoirs. Other references are predominantly concerned with counteracting the acidic and caustic irritation problems associated with water hydrolysis at the anode and cathode, respectively. Furthermore, the references have focussed primarily on donor (drug) reservoir pH control since the solubility of the drug in the liquid solvent is in many cases highly dependent on solution pH. Thus, minimizing skin irritation by control of counter reservoir pH has received only cursory attention in the prior art. Furthermore, previous disclosures relating to minimizing skin irritation from electrotransport devices have concentrated on the active or donor reservoir. However, electrotransport devices apply as much current through the counter electrode as through the donor electrode, and hence, skin irritation due solely to application of electric current also occurs beneath the counter reservoir or counter electrode. In a typical electrotransport device, the area of device/skin contact beneath the counter reservoir is nearly equivalent to the area beneath the donor reservoir. Hence, skin erythema, irritation, and/or damage in the counter reservoir contact area may be similar in magnitude to that in the donor reservoir contact area.